Zika virus (ZIKV) is an emerging flavivirus, and its ability to cause birth defects including microcephaly has raised global public health concern. ZIKV is primarily transmitted by the mosquito Aedes aegypti, but it has also been shown to be transmitted sexually from males to their uninfected partners and more recently from females to their uninfected partners. In order to further investigate ZIKV infection of the female reproductive tract and its consequences during pregnancy, we developed the first mouse model of vaginal infection by ZIKV. We find that the vagina is a susceptible route of infection and that vaginal ZIKV infection during pregnancy can lead to growth restriction and resorption of the fetus. We also identify the different components of the type I interferon (IFN) response that control vaginal ZIKV infection. In this proposal, I will use our recently-developed model to investigate how the type I IFN response prevents systemic spread of ZIKV and promotes fetal damage. My first aim is to investigate the innate mechanisms that control ZIKV viremia after vaginal infection. We see that mice lacking different components of viral recognition and type I Interferon (IFN) pathway have high levels of local viral replication after vaginal infection. However, only mice lacking the type I IFN receptor (and not some of the transcription factors and sensors upstream of IFN) develop systemic disease, including viremia, brain infection, and death. These findings indicate that there may be different components of the innate immune response control local and systemic ZIKV infection. In this aim, I will investigate how vaginal ZIKV exposure leads to systemic infection and how the immune response prevents systemic spread. My second aim is to determine the role of type I IFN signaling in mediating the pathology of the developing placenta and fetus. While type I IFN signaling is clearly important for protecting against spread of ZIKV and other viral infections, we see that type I IFN signaling in fetal-derived tissues mediates the severe pathology reported in ZIKV pregnancy models. In this aim, I will identify the defects in placental and fetal development that result from IFN signaling, and I will identify the cell types and interferon stimulated genes (ISGs) that mediate this damage induced by IFN in the placenta and fetus. This aim may give insight into how ZIKV and other viral infections lead to pregnancy complications such as intrauterine growth restriction and spontaneous abortion.